Neuropathic pain remains prevalent and challenging to manage and is often comorbid with depression and anxiety. The new approach that simultaneously targets neuropathic pain and the associated ...comorbidities, such as depression and anxiety, is timely and critical, given the high prevalence and severity of neuropathic pain and the lack of effective analgesics. In this review, we focus on the animal models of neuropathic pain that researchers have used to investigate the analgesic effects of cannabidiol (CBD) and Beta-Caryophyllene (BCP) individually and in combination while addressing the impact of these compounds on the major comorbidity (e.g., depression, anxiety) associated with neuropathic pain. We also addressed the potential targets/mechanisms by which CBD and BCP produce analgesic effects in neuropathic pain models. The preclinical studies examined in this review support CBD and BCP individually and combined as potential alternative analgesics for neuropathic pain while showing beneficial effects on depression and anxiety.
Cannabis contains over 500 distinct compounds, which include cannabinoids, terpenoids, and flavonoids. However, very few of these compounds have been studied for their beneficial effects. There is an ...emerging concept that the constituents of the cannabis plant may work in concert to achieve better therapeutic benefits. This study is aimed at determining if the combination of a minor cannabinoid (cannabidiol, CBD) and a terpene (beta-caryophyllene, BCP) works in concert and if this has any therapeutic value. We used an inflammatory pain model (formalin) in mice to test for any functionality of CBD and BCP in combination. First, we determined the analgesic effect of CBD and BCP individually by establishing dose-response studies. Second, we tested the analgesic effect of fixed-ratio combinations and monitored any adverse effects. Finally, we determined the effect of this combination on inflammation. The combination of CBD and BCP produces a synergistic analgesic effect. This effect was without the cannabinoid receptor-1 side effects. The analgesic effect of CBD and BCP in combination involves an inflammatory mechanism. The combination of these two constituents of the cannabis plant, CBD and BCP, works in concert to produce a therapeutic effect with safety profiles through an inflammatory mechanism.
Worldwide, women account for approximately 51% of human immunodeficiency virus-1 (HIV) seropositive individuals. The prevalence of neuropathic pain among individuals with HIV and a lack of ...preclinical data characterizing sex differences prompted us to address this knowledge gap. C57BL/6 male and female mice received multiple intrathecal injections of HIV-glycoprotein 120 (gp120), followed by determination of mechanical allodynia and thermal hypersensitivity for four weeks. The influence of ovarian hormones in the gp120 pain model was evaluated by comparison of ovariectomized (OVX) mice versus sham control. We found that gp120-induced neuropathic pain-like behaviors are sex-dependent. Female mice showed both increased mechanical allodynia and increased cold sensitivity relative to their male counterparts. The OVX mice showed reduced pain sensitivity compared to sham, suggesting a role of the ovarian hormones in sex differences in pain sensitivity to gp120. Gp120-induced neuropathic pain caused a shift in estrous cycle toward the estrus phase. However, there is a lack of clear correlation between the estrous cycle and the development of neuropathic pain-like behaviors during the four week recording period. This data provided the first evidence for sex differences in a rodent model of HIV-related neuropathic pain, along with a potential role of ovarian hormones.
Despite successful virologic control with combination antiretroviral therapy (cART), about half of people living with the human immunodeficiency virus-1 (HIV) develop an HIV-associated neurocognitive ...disorder (HAND). It is estimated that 50% of individuals who are HIV-positive in the United States are aged 50 years or older. Therefore, a new challenge looms as individuals living with HIV increase in age. There is concern that Alzheimer's disease (AD) may become prevalent with an earlier onset of cognitive decline in people living with HIV (PLWH). Clinical data studies reported the presence of AD biomarkers in PLWH. However, the functional significance of the interaction between HIV or HIV viral proteins and AD biomarkers is still not well studied. The main goal of the present study is to address this knowledge gap by determining if the HIV envelope glycoprotein 120 (HIV-gp120) can affect the cognitive functions in the Tau mouse AD model. Male Tau and age-matched, wild-type (WT) control mice were treated intracerebroventricularly (ICV) with HIV-gp120. The animals were evaluated for cognitive function using a Y-maze. We found that HIV-gp120 altered cognitive function in Tau mice. Notably, HIV-gp120 was able to promote a cognitive decline in transgenic Tau (P301L) mice compared to the control (HIV-gp120 and WT). We provide the first in vivo evidence of a cognitive interaction between an HIV viral protein and Tau mice.
The growing therapeutic use (self-medication) of cannabinoids by HIV-1 infected people and the recent interest in the possible medicinal use of cannabinoids, particularly in pain management, create ...an urgent need to identify their potential interactions with HIV-1. The goal here is to determine any interaction between proteins of HIV-1 and the analgesic effectiveness of cannabinoid at supraspinal level. Young adult male rats (Sprague-Dawley) were stereotaxically pretreated with HIV-1 envelope glycoprotein 120 (gp120) into the periaqueductal gray (PAG) area, the primary control center of pain modulation. Then, we examined its effect on cannabinoid receptor agonist WIN55,212-2-induced analgesia. Our results demonstrated that gp120 in PAG diminished the analgesic effectiveness of this cannabinoid agonist. These results suggest that gp120 may interact with the cannabinoid system through the descending modulatory pain pathways centered in the PAG to impair the analgesic effectiveness of cannabinoids.
Emerging evidence indicates the involvement of GPR55 and its proposed endogenous ligand, lysophosphatidylinositol (LPI), in nociception, yet their role in central pain processing has not been ...explored. Using Ca(2+) imaging, we show here that LPI elicits concentration-dependent and GPR55-mediated increases in intracellular Ca(2+) levels in dissociated rat periaqueductal gray (PAG) neurons, which express GPR55 mRNA. This effect is mediated by Ca(2+) release from the endoplasmic reticulum via inositol 1,4,5-trisphosphate receptors and by Ca(2+) entry via P/Q-type of voltage-gated Ca(2+) channels. Moreover, LPI depolarizes PAG neurons and upon intra-PAG microinjection, reduces nociceptive threshold in the hot-plate test. Both these effects are dependent on GPR55 activation, because they are abolished by pretreatment with ML-193 N-(4-(N-(3,4-dimethylisoxazol-5-yl)sulfamoyl)-phenyl)-6,8-dimethyl-2-(pyridin-2-yl)quinoline-4-carboxamide, a selective GPR55 antagonist. Thus, we provide the first pharmacological evidence that GPR55 activation at central levels is pronociceptive, suggesting that interfering with GPR55 signaling in the PAG may promote analgesia.
Growing evidence supports the idea that in addition to their well established role in the immune system, chemokines might play a role in both normal and pathological brain function, and the chemokine ...network could interact with other neuromodulators. The chemokine stromal cell-derived growth factor (SDF)-1alpha/CXCL12, a member of the CXC chemokine family, was tested for its possible effect on the analgesic responses of the cannabinoid receptor agonist aminoalkylindole 4,5-dihydro-2-methyl-4-(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo-3,2,1ijquinolin-6-one (+)-WIN 55,212-2, hereafter WIN 55,212-2 at the level of the periaqueductal gray (PAG), a brain region critical to the processing of pain signals, and a primary site of action of many analgesic compounds. The administration of WIN 55,212-2 (0.1-0.4 microg/microl) into the PAG resulted in antinociception in a dose-dependent manner. The selective cannabinoid (CB)1 antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR 141716A; 1-10 microg) given into the PAG blocked the WIN 55,212-2-induced antinociception. In contrast, the selective CB2 antagonist N-(1S)-endo-1,3,3-trimethyl bicyclo heptan-2-yl-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528; 10 microg) did not alter the WIN 55,212-2-induced antinociception. Pretreatment with SDF-1alpha/CXCL12 (100 ng) caused a reduction in antinociceptive responses of WIN 55,212-2. The inhibitory effect of SDF-1alpha/CXCL12 on WIN 55,212-2-induced antinociception was reversed by octahydrochloride corrected hydrate (AMD 3100) (10-50 ng), an antagonist of the SDF-1alpha/CXCL12, acting at its receptor, CXCR4. This study reports the first in vivo evidence of a functional interaction between chemokine and cannabinoid systems in the brain, showing that the activation of SDF-1alpha/CXCL12 receptors (CXCR4) in the PAG interferes with the analgesic effects of WIN 55212-2.
The widespread abuse of 3,4-methylenedioxymethamphetamine (MDMA) has intensified the need to learn more about this drug (e.g. its effects, its mechanism of action, brain areas affected). MDMA-induced ...hyperthermia is a severe physiological event not only because it can produce severe adverse consequences in human as well as experimental animals, but also because it plays a major role in determining the severity of the long-term MDMA-induced neurotoxicity that occurs. However, the effects of MDMA on the preoptic anterior hypothalamus, the main brain area responsible for control of body temperature, are still unknown. In vivo microdialysis–biotelemetry and pharmacological testing were used to determine whether the preoptic anterior hypothalamus is among the brain areas affected by MDMA by investigating the role of the dopamine neurotransmitter system. We examined the effect of a hyperthermic dose of MDMA on the extracellular level of dopamine in the preoptic anterior hypothalamus, and whether this effect is related to the acute hyperthermic response. The administration of a hyperthermic dose of MDMA (20 mg/kg) is accompanied by an increase in the extracellular level of dopamine in the preoptic anterior hypothalamus. Both the hyperthermia and augmented level of dopamine in the preoptic anterior hypothalamus after intraperitoneal injection of MDMA were significantly reduced by the pretreatment with D
1-selective dopamine receptor antagonist,
R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1
H-3-benzapine (SCH 23390). These data provide the first in vivo evidence that the effects of MDMA extend to preoptic anterior hypothalamus.
Chronic pain, one of the most common reasons adults seek medical care, has been linked to restrictions in mobility and daily activities, dependence on opioids, anxiety, depression, sleep deprivation, ...and reduced quality of life. Alzheimer's disease (AD), a devastating neurodegenerative disorder (characterized by a progressive impairment of cognitive functions) in the elderly, is often co-morbid with chronic pain. AD is one of the most common neurodegenerative disorders in the aged population. The reported prevalence of chronic pain is 45.8% of the 50 million people with AD. As the population ages, the number of older people who experience AD and chronic pain will also increase. The current treatment options for chronic pain are limited, often ineffective, and have associated side effects. This review summarizes the role of the endocannabinoid system in pain, its potential role in chronic pain in AD, and addresses gaps and future directions.
•Chronic pain is a major health issue•Alzheimer's disease (AD), a devastating neurodegenerative disorder•The reported prevalence of chronic pain is 45.8% of the 50 million people with AD worldwide.•The current treatment options for chronic pain are limited, often ineffective, and have associated side effects.•This review explores the endocannabinoid system's role in pain, its potential role in chronic pain management in AD.
There is a clear need for novel and improved therapeutic strategies for alleviating chronic neuropathic pain, as well as a need for better understanding of brain mechanisms of neuropathic pain, which ...are less understood than spinal and peripheral mechanisms. The G protein-coupled receptor 55 (GPR55), is a lysophosphatidylinositol (LPI)-sensitive receptor that has also been involved in cannabinoid signaling. It is expressed throughout the central nervous system, including the periaqueductal gray (PAG), a brainstem area and key element of the descending pain control system. Behaviors, pharmacology, biochemistry tools, and stereotaxic microinjections were used to determine if GPR55 plays a role in pain control in a chronic constriction injury (CCI) neuropathic pain model in rats. It was found that the blockade of GPR55 action in the PAG can restore and drive a descending control system to mitigate neuropathic pain.
Our data demonstrate that GPR55 play a role in the descending pain control system, and identify GPR55 at supraspinal level as a neuropathic pain brain mechanism.
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